Investigating the role of Growth-differentiation factor 11 in neurodevelopmental and MECP2-related disorders

研究生长分化因子 11 在神经发育和 MECP2 相关疾病中的作用

基本信息

批准号：
10022128
负责人：
Sameer Bajikar
金额：
$ 6.93万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-10 至 2022-03-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022128
关键词：
Acute Address Alleles Anxiety Behavior Binding Proteins Brain Brain region Brain-Derived Neurotrophic Factor Catalogs Computer Models DNA Data Set Defect Dendrites Development Developmental Delay Disorders Disease Dose Family Fellowship GDF11 gene Gene Expression Genes Genetic Goals Growth Factor Human IGF1 gene Individual Intellectual functioning disability Knock-out Knockout Mice Language Lead Learning Ligands Live Birth MeCP2 Duplication Syndrome Memory Meta-Analysis Methods Methyl-CpG-Binding Protein 2 Modeling Molecular Morphology Motor Mus Mutation Neurodevelopmental Disorder Neurologic Neuronal Dysfunction Neurophysiology - biologic function Nuclear Protein Pathogenesis Patients Pattern Perinatal Phenotype Play Proteins Recombinants Regulation Rett Syndrome Role Sampling Seizures Skeletal system Social Behavior Stereotyped Behavior Syndrome Testing Therapeutic Tissues Transcript Transforming Growth Factor beta Transgenic Model Viral Work age related behavior test disease phenotype improved in vivo insight loss of function mutation morphogens mouse Cre recombinase mouse methyl CpG binding protein 2 mouse model nerve stem cell nervous system disorder neurodevelopment neurogenesis neuropathology novel therapeutics pre-clinical prevent relating to nervous system targeted treatment transcriptome transcriptome sequencing virus genetics

项目摘要

PROJECT SUMMARY Loss-of-function mutations or duplication in methyl-CpG binding protein 2 (MECP2) cause two severe neurodevelopmental disorders: Rett syndrome and MECP2 duplication syndrome, respectively. While the genetic cause of these disorders is known, the mechanism by which disruption in MECP2 leads to pathogenesis is unknown; this has prevented the development of targeted therapies. Treatment with secreted factors has shown some efficacy in preclinical mouse models of MECP2-disorders. To identify candidate secreted factors misregulated by MeCP2, transcriptome profiles collected from Mecp2-null mouse models were evaluated, and Growth differentiation factor 11 (GDF11) was identified as a growth factor sensitive to MECP2-levels. GDF11 is downregulated in Mecp2-null models, while upregulated in MECP2-transgenic models. The opposing regulation of GDF11 by MECP2 implicates GDF11 misregulation as one potential shared mechanism between Rett and MECP2 duplication syndromes. GDF11 is a transforming growth factor beta family ligand that is a critical patterning morphogen for the skeletal system. However, despite broad expression throughout the brain, the role of GDF11 in brain development is unknown. The work proposed in this fellowship will test the hypothesis that GDF11 is a key morphogen for brain development, and that its misregulation in models of MECP2-disorders contributes to MECP2-disorder phenotypes. This hypothesis will be tested through the following specific aims: 1. Test if modulating brain specific dose of GDF11 by viral or genetic methods itself causes aberrant neurological phenotypes. 2. Test if normalization of GDF11 levels rescues neurological phenotypes seen in mouse models of MECP2- disorders. 3. Test the regulatory relationship between MECP2 and GDF11 by modeling the temporal changes in the transcriptome after perturbation of MECP2-levels to identify primary gene expression changes. The results from this fellowship will address three key questions in the field: 1) is GDF11 dose important in brain development, 2) does rescue of GDF11-levels ameliorate phenotypes in mouse models of MECP2-disorders, and 3) what are the primary gene expression changes that occur upon modulation of MECP2 levels.

项目摘要甲基-CPG结合蛋白2（MECP2）中功能丧失突变或复制导致两个严重神经发育障碍：RETT综合征和MECP2重复综合征。而这些疾病的遗传原因是已知的，这是MECP2中破坏导致发病机理的机制是未知的；这阻止了靶向疗法的发展。分泌因素的治疗有在MECP2抑制剂的临床前小鼠模型中显示了一些功效。确定候选人的分泌因素由MECP2误导，评估了从MECP2无效小鼠模型收集的转录组轮廓，并生长分化因子11（GDF11）被确定为对MECP2级敏感的生长因子。 GDF11是在MECP2-NULL模型中下调，而在MECP2转基因模型中被上调。反对法规 MECP2的GDF11的GDF11暗示了GDF11的不调节是RETT和RETT和 MECP2复制综合征。 GDF11是一个转变的生长因子β家族配体，这是关键用于骨骼系统的形态形态。然而，尽管整个大脑中的表现都广泛，但角色 GDF11在大脑发育中的发展尚不清楚。该奖学金中提出的工作将检验以下假设：GDF11是大脑的关键形态学开发，并且它在MECP2-Disorders模型中的正直有助于MECP2 disorder 表型。该假设将通过以下特定目的进行检验： 1。测试是否通过病毒或遗传方法调节大脑特异性GDF11本身会导致异常神经表型。 2。测试如果GDF11水平的归一化，可以挽救MECP2-小鼠模型中看到的神经表型。疾病。 3。通过对MECP2和GDF11之间的调节关系进行建模 MECP2级扰动后的转录组，以鉴定基本基因表达变化。该奖学金的结果将解决该领域的三个关键问题：1）GDF11剂量在大脑中很重要开发，2）在MECP2降低的小鼠模型中，拯救GDF11级级别的表型， 3）在调制MECP2水平时发生的主要基因表达发生了什么变化。